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Amino Acid Metabolism Student Edition 6/3/13 version
Pharm. 304 Biochemistry
Fall 2014
Dr. Brad Chazotte 213 Maddox Hall
[email protected] Site:
http://www.campbell.edu/faculty/chazotte
Original material only ©2004-14 B. Chazotte
Goals
• Understand the relationship of nitrogen to carbon intermediary metabolism.
• Learn the Urea Cycle sequence, reactions, and products.• Have an understanding of an overview of amino acid
catabolism resulting in 7 basic products and the difference between ketogenic and glucogenic catabolism.
• Have an understanding of an overview of amino acid anabolism from basic precursors.
• Understand the concept of essential and nonessential amino acids in the diet of humans.
• Understand that many diseases can arise from errors in amino acid metabolism.
Do NOT memorize any of the specific amino acid catabolic or anabolic pathways. They are for informational purposes only.
Nitrogen Pathways in
Intermediary Metabolism
Matthews et al 2000 Figure 20.1
Plants
Dietary Amino Acids in Metabolism
“Excess dietary amino acids are not simply excreted but are converted to common metabolites that are precursors of glucose, fatty acids, ketone bodies – and are therefore metabolic fuels”
Voet, Voet & Pratt 2008 p.732
Protein Synthesis & Degradation
1. Nutrient storage as protein; break proteins down in times of metabolic need (muscle a prime source)
2. Eliminate accumulation of abnormal proteins that would harm the cell
3. Permit the regulation of cellular metabolism by the elimination of unneeded enzymes and regulatory proteins.
Voet, Voet & Pratt 2008 p.733
Catabolism
Cellular Protein Degradative Routes Lysosomal - a cellular compartment at ~pH 5 containing hydrolytic enzymes (cathepsins). Degrade substances taken up by endocytosis. Recycle intracellular constituents enclosed within vacuoles. In “well nourished cells” protein degradation is nonselective. In starving cells a selective pathway is activated that imports and degrades proteins that contain the pentapeptide (Lys-Phe-Glu-Arg-Gln; KFERQ) e.g., in muscle and liver, but not brain.
Ubiquitin-Based – ATP-based process independent of lysosomes. Proteins are marked for degradation by linking to ubiquitin.
Rx Involved in Protein Ubiquination
Voet, Voet & Pratt 2013 Fig 21.2 Matthews et al 2000 Figure 20.11
Matthews et al 2000 Figure 20.10
Proteasome
Voet, Voet & Pratt 2013 Fig 21.4
Distinguishing Protein Lifetimes
The N-end Rule:
N-terminal residues Asp, Arg, Leu, Lys & Phe
half-life ~ 2-3 minutes
Ala, Gly, Met, Ser Thr, & Val
half-life > 20 hrs in eukaryotes
(>10 prokaryotes)
PEST proteins Proteins with segments rich in Pro, Glu, Ser, & Thr are rapidily degraded- these AA have sites that can be phosphorylated – thus targeting them for ubiquitination.
Voet, Voet & Pratt 2013 Table 21.1
Some Cellular Processes Regulated by Protein Degradation
e.g,NF-κB –I κB system
Berg, Tymoczko, & Stryer 2012 Table 23.3
Protein (“Macro”)
Digestion in the Human
Gastrointestinal Tract
Lehninger 2000 Figure 18.3Berg, Tymoczko, & Stryer 2012 Figure 23.1
Amino Acid Catabolism: Overview
Voet, Voet & Pratt 2013 Fig 21.6Lehninger 2004 Figure 18.1
Amino acid degradation includes a key step of separating the amino group from the carbon skeleton.
Amino Acid Deamination Transamination - most amino acids are deaminated by this process carried out by transaminases (aminotransferases). Amino group of amino acid is transferred (predominately) to -ketoglutarate
Oxidative Deamination – of glutamate by glutamate dehydrogenase yields ammonia and -ketoglutarate
Voet, Voet & Pratt 2013 Chap. 21 page 722
Voet, Voet & Pratt 2013 Chap. 21 page 719
Forms of Pyridoxal-5’-Phosphate
Voet, Voet & Pratt 2013 Fig 21.7
Needed by aminotransferases as a coenzyme.
PLP-Dependent Enzyme Catalyzed Transamination Mechanism
Voet, Voet & Pratt 2013 Fig 21.8
Oxidative Degradation of Amino Acids
Occurs under three different circumstances in animals:
1) During normal homeostasis
2) Protein-rich diet
3) Starvation or uncontrolled diabetes mellitus
Lehninger 2000 Chapter 18
Glutamate Dehydrogenase (Oxidative Deamination)
A mitochondrial enzyme yielding ammonia and -ketoglutarate
It is the only enzyme that can accept either NAD+ or NADP+ as a coenzyme
G° = ~30 kJ mol-1
Due to the high toxicity of ammonia – it is important that under physiological conditions G ≈ 0, i.e. at equilibrium.
Lehninger 2000 Figure 18.7
mammalian liver
Ammonia Transport to Liver for Urea Synthesis
Matthews et al 2000 Figure 20.14 Lehninger 2000 Figure 18.8
Urea Cycle
Urea Cycle Enzymes
(1) Carbamoyl Phosphate synthetase (mitochondrion)
(2) Ornithine transcarbamoylase (mitochondrion)
(3) Argininosuccinate synthetase (cell cytosol)
(4) Argininosuccinase (cell cytosol)
(5) Arginase (cell cytosol)
Overall Urea Cycle Reaction
Voet, Voet & Pratt 2013 Chap 21 p 723
Urea Cycle & Feeder Reactions
Voet, Voet & Pratt 2013 Fig 21.9
Lehninger 2000 Figure 18.9
Urea Cycle Diagram
Lehninger 2000 Figure 18.9
Nitrogen-acquiring reactions in Urea Synthesis
Lehninger 2004 Figure 18.11
Linking the Urea & Citric Acid Cycles“ Krebs ‘Bicycle’ ”
Lehninger 2004 Figure 18.12
AA Degradation to 1 of 7 Common Intermediates
Voet, Voet & Pratt 2013 Fig 21.13
Glucogenic vs Ketogenic Amino Acid Degradation
• Glucogenic - degradation lead to glucose precusors: pyruvate, α-ketoglutarate, succinyl-CoA, fumarate or oxaloacetate
• Ketogenic – degradation leads to fatty acids or ketone body precursors: acetyl-CoA or acetoacetate
• Some amino acids are gluco- and keto-genic
Examples of a Few Disorders of Human Amino Acid Catabolism
Lehninger 2000 Table 18.2
PKU
Tyrosimenia I, II, or III Rx 5, 2, or 4- respectively {side 35}
Anabolism
Human Essential & Non-Essential Amino Acid
Voet, Voet & Pratt 2013 Table 21.3
Amino Acid Biosynthetic Families
Lehninger 2000 Table 22.1
CAC
CAC
Glycolysis
Glycolysis
PP
PP
Metabolic Relationships Among Amino Acids Derived from Citric Acid Cycle
Intermediates
Matthews et al 2000 Figure 21.1
Essential Human amino acid
THOSE AA HIGHLIGTED BY AN ORANGE BOX ARE ESSENTIAL AMINO ACIDS FOR HUMANS.
Biosynthesis of Non-Essential Amino Acids
With the exception of tyrosine, all the nonessential amino acids come from one these four metabolic intermediates: pyruvate, oxaloacetate, α-ketoglutarate, and 3-phosphoglycerate.
End of Lecture Materials
Supplementary Material on Amino Acid Catabolism
• This material will NOT be on any test and is for informational purposes only.
Pathways for Ala, Cys, Gly, Ser & Thr to Pyruvate
Voet, Voet & Pratt 2008 Fig 21.14
Serine Dehydratase
Voet, Voet & Pratt 2008 Fig 21.15
Pathways for Arginine,
Glutamate, Glutamine, Histidine & Proline to -
ketoglutarate
Voet, Voet & Pratt 2008 Fig 21.17
Methionine Degradation
Voet, Voet & Pratt 2008 Fig 21.18
TetraHydroFolate
Voet, Voet & Pratt 2008 Table 21.2, Fig 21.19
2-State Reduction of Folate to THF
Branched-Chain AA Degradation
Voet, Voet & Pratt 2008 Fig 21.21
Mammalian Liver Lysine Degradation
Voet, Voet & Pratt 2008 Fig 21.22
Saccharopine dehydrogenase
Saccharopine dehydrogenase
aminoadipate semialdehyde dehydrogenase
Sminoadipate amino- transferase
Α-keto acid dehydrogenase
Glutaryl-CoA dehyd.
decarboxylaseEnoyl-CoA dehydratase
Β-hydrozyacylCoA dehydrogenase
HMG-CoA synthase
HMG-CoA lyase
1
Tryptophan Degradation
Voet, Voet & Pratt 2008 Fig 21.23
Tryptophan-2,3- dioxygenase
formamidase
Kynureninase-3- monooxygenase
Kynureninase
Phenylalanine Degradation
Voet, Voet & Pratt 2008 Fig 21.24
Phenylalanine hydroxylase
Tyrosine aminotransferase
p-hydroxyphenyl pyruvate dioxygenase
Homogentisate dioxygenase
fumarylacetoacetase
Supplementary Information of Amino Acid Anabolism
• The information in the slides hereafter is for informational purposes only, if you are interested, and will NOT be part of any test.
• Amino acid degradative and biosynthetic pathways are sites for a significant number of illnesses and/or genetic defects.
Alanine, Aspartate, Glutamate, Asparagine
& Glutamine Syntheses (Non-essential)
Voet, Voet & Pratt 2008 Fig 21.27
Glutamate “Family” Syntheses:Arginine, Ornithine & Proline
Voet, Voet & Pratt 2008 Fig 21.30
γ-glutamyl kinase
Glutamate dehydrogenase
Pyrroline carboxylate reductase
Path in mammals
3-Phosphoglycerate Serine Conversion
Voet, Voet & Pratt 2008 Figure 21.31
3-phosphoglycerate dehydrogenase
Phosphoserine aminotransferase
Phosphoserine phosphotase
Biosynthesis of Essential Amino Acids
Biosyntheses of Aspartate “Family”:
Lysine, Methionine, & Threonine
Voet, Voet & Pratt 2008 Fig 21.32
Biosyntheses of the
Pyruvate “Family”: Isoleucine, leucine &
Valine
Voet, Voet & Pratt 2008 Figure 21.33
Biosyntheses of
Phenylalanine, Tryptophan, & Tyrosine
Voet, Voet & Pratt 2008 Fig 21.34
Biosynthesis of Histidine
Voet, Voet & Pratt 2008 Fig 21.36
Heme Biosynthesis
Voet, Voet & Pratt 2008 Fig 21.38
Summary: Glucogenic
& Ketogenic Amino Acids
Lehninger 2000 Figure 18.29
Amino Acid Biosynthesis: Overview I
Lehninger 2000 Figure 22.9a
Amino Acid Biosynthesis: Overview II
Lehninger 2000 Figure 22.9b
Amino Acid Biosynthesis: Overview III
Lehninger 2000 Figure 22.9c
End of Supplementary Material